2-substituted pregna-1,3,5(10) triene and chola-1,3,5(10) triene derivatives and their biological activity

ABSTRACT

Compounds of formula (I) in which: R 1  represents a hydrogen atom or an O-protecting group; R 2  represents a hydroxyl, lower alkoxy, carboxaldehyde, lower alk-1-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group; R 3  represents a methyl group having α- or β-configuration; X represents a C 1-3  alkylene group or a valence bond; Y represents a carboxaldehyde group or a group of formula —C(R 4 )(R 5 )OR 1  where R 1  is as defined above and R 4  and R 5 , which may be the same or different, are each selected from hydrogen atoms, alkyl, alkenyl and alkynyl groups such that the total carbon content of R 4  and R 5  does not exceed three atoms, with the proviso that X is a valence bond when both R 4  and R 5  are other than hydrogen; and the dotted line signifies that a double bond may optionally be present at the 16(17)-position exhibit potent cell modulating activity, including antiproliferative and antiangiogenic effects.

[0001] This invention relates to novel sterol derivatives, moreparticularly to 2-substituted ring A aromatic sterol derivatives havinga comparatively short 17-position hydrocarbyl side chain whichterminates in an carboxaldehyde group or an optionally substitutedhydroxyl group. Such compounds have been found to have cell modulatingactivity and may exhibit valuable antiproliferative and antiangiogeniceffects.

[0002] WO-A-0068246 discloses a range of 3-sterols and O-protectedderivatives having an aromatic A-ring and a 17-position side chain whichterminates with an amine, amide or hydroxyl group attached to a tertiarycarbon atom. These compounds exhibit potent effects on the modulation ofcell growth and differentiation, for example as demonstrated by theirability to inhibit growth of cancer cells in vitro and in vivo, whilepossessing an advantageous therapeutic ratio by virtue of their lowlevels of calcaemic activity, for example as determined by their effectson serum calcium and phosphorus levels in rats. In this respect theactivity of the compounds resembles that of various vitamin D analoguesdespite the fact that they have an intact tetracyclic nucleus and lackboth the seco steroid triene system of vitamin D analogues and theability to mimic a conjugated conformational isomer thereof.

[0003] It is also known that 2-methoxyoestradiol, which like2-methoxyoestrone is a natural metabolite of oestradiol, preventsproliferation and promotes the death of cancer cells in vivo. Studieshave suggested that these effects are at least in part mediated byinhibition or misdirection of tubulin polymerisation in a manner similarto that exhibited by colchicine; thus the metabolite has been observedto bind to the colchicine binding site of tubulin.

[0004] As noted by Cushman et al. in J. Med. Chem. 38(12), pp. 2041-2049[1995], 2-methoxyoestradiol has also been found to inhibit angiogenesis(the creation of new blood vessels); this is potentially an extremelyvaluable property in cancer treatment, since angiogenesis is requiredfor the growth of solid tumours. Both Cushman et al. (op. cit.) andLovely et al. in J. Med. Chem. 39(9), pp. 1917-1923 [1996] report thesynthesis and evaluation for cytotoxicity of various 2-methoxyoestradiolanalogues; all the compounds investigated were 17-ones or optionallysubstituted 17-ols.

[0005] The antiproliferative and antiangiogenic effects of2-methoxyoestradiol are discussed by Pribluda et al. in Cancer andMetastatic Reviews 19(1-2), pp. 173-179 [2000], where it is stated thatit targets both tumour cell and endothelial cell compartments byinducing apoptosis in rapidly proliferating cells and inhibiting bloodvessel formation at several stages in the angiogenic cascade. It is alsosaid to inhibit metastatic spread in several models.

[0006] Dubey et al. in Biochem. Biophys. Comm. 278(1), pp. 27-33 [2000]report that endogenous methoxyoestradiols mediate the antimitogeniceffects of oestradiol on vascular smooth muscle cells via oestrogenreceptor-independent mechanisms.

[0007] WO-A-9933859 discloses a variety of 1,3,5-oestratrienes havingheteroatom-containing hydrocarbyl side chains at the 17-position. Thecompounds are said to be oestrogen antagonists and there is nosuggestion that they may exhibit antiproliferative or antiangiogeniceffects or colchicine-like interference with tubulin polymerisation.

[0008] WO-A-9933858 discloses 3-sulphamoyloxy-1,3,5-oestratrienes whichcontain relatively short hydrocarbyl side chains at the 17-position andwhich are said to act as inhibitors of steroidal sulphatase enzymes.Again there is no suggestion that they may exhibit antiproliferative orantiangiogenic effects or colchicine-like interference with tubulinpolymerisation.

[0009] The present invention is based on the unexpected finding that arange of 2-substituted ring A aromatic sterol derivatives having acomparatively short 17-position hydrocarbyl side chain which terminatesin a carboxaldehyde (—CHO) group or an optionally O- and/orC-substituted hydroxymethyl group exhibit potent cell modulatingactivity. Tissue culture assays show such compounds to exhibit doseresponse curves characteristic of colchicine, suggesting that theirantiproliferative activity derives at least in part from colchicine-likeinterference with tubulin polymerisation. Compounds of the invention maytherefore inhibit angiogenesis in analogous but more potent mannercompared to compounds such as 2-methoxyoestradiol. The compounds alsoshow reduced but still significant binding to oestrogen receptors,suggesting that they may have further applications analogous to those ofother non-uterotrophic oestrogen response modulators.

[0010] According to one embodiment of the invention there are providedcompounds of formula (I)

[0011] in which:

[0012] R¹ represents a hydrogen atom or an O-protecting group;

[0013] R² represents a hydroxyl, lower alkoxy, carboxaldehyde, loweralk-1-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group;

[0014] R³ represents a methyl group having α- or β-configuration;

[0015] X represents a C₁₋₃ alkylene group or a valence bond;

[0016] Y represents a carboxaldehyde group or a group of formula—C(R⁴)(R⁵)OR¹ where R¹ is as defined above and R⁴ and R⁵, which may bethe same or different, are each selected from hydrogen atoms, alkyl,alkenyl and alkynyl groups such that the total carbon content of R⁴ andR⁵ does not exceed three atoms, with the proviso that X is a valencebond when both R⁴ and R⁵ are other than hydrogen; and

[0017] the dotted line signifies that a double bond may optionally bepresent at the 16(17)-position.

[0018] O-protecting groups present as R¹ groups may, for example,comprise any suitable cleavable O-protecting group such as is known inthe art. Representative groups include (i) etherifying groups such assilyl groups (e.g. tri(lower alkyl)silyl groups such as trimethylsilyl,triethylsilyl, triisopropylsilyl or t-butyldimethylsilyl; tri(aryl)silylgroups such as triphenylsilyl; and mixed alkyl-arylsilyl groups), lower(e.g. C₁₋₆) alkyl groups optionally interrupted by an oxygen atom (e.g.such as methyl, ethyl, methoxymethyl or methoxyethoxymethyl) orsubstituted by a lower (e.g. C₃₋₈) cycloalkyl group (e.g. as incyclopentylmethyl) or by an acyloxy group (e.g. by a lower alkanoyloxygroup, for example as in pivaloyloxymethyl), and cyclic ether groups(e.g. such as tetrahydropyranyl), and (ii) esterifying groups such aslower (e.g. C₁₋₆) alkanoyl (e.g. such as acetyl, propionyl, isobutyryl,pivaloyl or hemisuccinyl), aroyl (e.g. containing 7-15 carbon atoms,such as benzoyl or 4-phenylazobenzoyl), lower (e.g. C₁₋₆) alkanesulphonyl (e.g. such as methane sulphonyl or halogenated methanesulphonyl), arene sulphonyl (e.g. such as p-toluene sulphonyl), andsulphamoyl, for example groups of formula (R⁶)(R⁷)N.SO₂— where R⁶ and R⁷are each independently selected from hydrogen atoms and lower (e.g.C₁₋₆) alkyl groups or together form a lower (e.g. C₃₋₁₀) alkylene chainoptionally interrupted by one or more heteroatoms selected from O, N andS. It will be appreciated that R¹ at the 3-position may be the same asor different from any R¹ the 17-position side chain.

[0019] Where R² represents a lower alkoxy group, this may for example bea straight chain or branched C₁₋₆ alkoxy group such as a methoxy, ethoxyor propoxy group. Lower alk-1-enyl groups may, for example, contain 2-6carbon atoms, e.g. as in vinyl, prop-1-enyl and but-1-enyl groups.Representative hydroxy- and lower alkoxy-substituted lower alkyl groupsinclude hydroxymethyl, 1- and 2-hydroxyethyl, 1-, 2- and 3-hydroxypropyland corresponding methoxy- and ethoxy-substituted groups. Loweralkoxy-substituted lower alkyl groups preferably contain up to 6 carbonatoms in total.

[0020] Where R³ in formula (I) is a methyl group in the α-configuration,the compounds have the 20R configuration characteristic of naturalsterols such as cholesterol; where R³ is in the β-configuration thecompounds have the 20S configuration of the correspondingepi-derivatives. It will be appreciated that the invention also embracesmixtures of the two isomers.

[0021] Where X is an alkylene group this may, for example, be amethylene, ethylene or trimethylene group.

[0022] Where Y represents a group of formula —C(R⁴)(R⁵)OR¹ this mayadvantageously be an optionally O-protected hydroxymethyl group or asubstituted hydroxymethyl group in which one of R⁴ and R⁵ is methyl,ethyl, vinyl, ethynyl or propargyl and the other is hydrogen, or inwhich R⁴ and R⁵ are both methyl.

[0023] Compounds of formula (I) in which R¹ is hydrogen, a metabolicallylabile O-protecting group (e.g. a lower alkanoyl group such as acetyl orhemisuccinyl; an acyloxymethyl group, for example a loweralkanoyloxymethyl group such as pivaloyloxymethyl; or a sulphonyl group,for example as in a sulphate or sulphamate group) or a lower alkyletherifying O-protecting group such as methyl, ethyl or isobutyl may beuseful directly in therapy. The use of compounds in which R¹ is abiolabile sulphamoyl group may be advantageous, since such groups willtend to inhibit steroid sulphatases which may otherwise degradesteroid-3-ols formed upon removal of such a protecting group from the3-position. Compounds (I) containing non-metabolically labileO-protecting groups (e.g. bulky silyl ether groups such as triisopropyl,t-butyldimethylsilyl or triphenylsilyl) are principally of use assynthetic intermediates.

[0024] The cell modulating activity of active compounds according to theinvention, combined with their substantial lack of adverse side effects,render them of interest both alone and as adjuncts in the management ofdiseases associated with abnormal cell proliferation, such as neoplasticdisease, particularly myelogenous leukemias as well as neoplasticdisease of the brain, breast, stomach, gastrointestinal tract, prostate,pancreas, uro-genital tract (male and female) and pulmonary neoplasia.Their ability to promote closure of mouse ear puches suggests their use,either alone or as adjuncts, as agents to promote wound healing.

[0025] Their cell modulating activity suggests that active compounds ofthe invention may, like other oestrogen response modulators, haveadditional utilities either alone or as adjuncts in the chemotherapy ofinfection and in other therapeutic modalities in which mononuclearphagocytes are involved, for example in treatment of bone disease(especially osteoporosis, osteopenia and osteodystrophy as in rickets orrenal osteodystrophy), autoimmune disease, host-graft reaction,transplant rejection, inflammatory diseases (including modulation ofimmunoinflammatory reactions), neoplasias and hyperplasias, theirpotential utility in treatment of neoplasias and hyperplasias beingevidenced by their ability to inhibit growth of a variety of humancancer cells. Additionally, they may be useful in treatment ofdermatological diseases (for example including acne, alopecia, eczema,pruritus, psoriasis and skin aging, including photoaging), hypertension,rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairmentand senile dementia (including Alzheimer's disease), in fertilitycontrol in both human and animal subjects, in lowering elevated serumcholesterol, and in management of disorders involving blood clotting(e.g. by dissolution of existing clots and/or by prevention ofclotting). The invention embraces use of these compounds in the therapyor prophylaxis of such conditions and in the manufacture of medicamentsfor use in such treatment or prophylaxis.

[0026] Active compounds according to the invention may be formulated foradministration by any convenient route, e.g. orally (includingsublingually), parenterally, rectally or by inhalation; pharmaceuticalcompositions so formulated comprise a feature of the invention.

[0027] Orally administrable compositions may, if desired, contain one ormore physiologically compatible carriers and/or excipients and may besolid or liquid. The compositions may take any convenient formincluding, for example, tablets, coated tablets, capsules, lozenges,aqueous or oily suspensions, solutions, emulsions, syrups, elixirs anddry products suitable for reconstitution with water or another suitableliquid vehicle before use. The compositions may advantageously beprepared in dosage unit form. Tablets and capsules according to theinvention may, if desired, contain conventional ingredients such asbinding agents, for example syrup, acacia, gelatin, sorbitol, tragacanthor polyvinyl-pyrollidone; fillers, for example lactose, sugar,maize-starch, calcium phosphate, sorbitol or glycine; lubricants, forexample magnesium stearate, talc, polyethylene glycol or silica;disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulphate. Tablets may be coated according tomethods well known in the art.

[0028] Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxymethylcellulose,carboxymethylcellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate oracacia; non-aqueous vehicles, which may include edible oils, for examplevegetable oils such as arachis oil, almond oil, fractionated coconutoil, fish-liver oils, oily esters such as polysorbate 80, propyleneglycol, or ethyl alcohol; and preservatives, for example methyl orpropyl p-hydroxybenzoates or sorbic acid. Liquid compositions mayconveniently be encapsulated in, for example, gelatin to give a productin dosage unit form.

[0029] Compositions for parenteral administration may be formulatedusing an injectable liquid carrier such as sterile pyrogen-free water,sterile peroxide-free ethyl oleate, dehydrated alcohol or propyleneglycol or a dehydrated alcohol/propylene glycol mixture, and may beinjected intravenously, intraperitoneally or intramuscularly.

[0030] Compositions for rectal administration may be formulated using aconventional suppository base such as cocoa butter or another glyceride.

[0031] Compositions for administration by inhalation are convenientlyformulated for self-propelled delivery, e.g. in metered dose form, forexample as a suspension in a propellant such as a halogenatedhydrocarbon filled into an aerosol container provided with a meteringdispense valve.

[0032] It may be advantageous to incorporate an antioxidant, for exampleascorbic acid, butylated hydroxyanisole or hydroquinone in thecompositions of the invention to enhance their storage life.

[0033] Where any of the above compositions are prepared in dosage unitform these may for example contain 2 μg-100 mg of active compoundaccording to the invention per unit dosage form; such dosage units mayfor example be administered 1-4 times per day. The compositions may ifdesired incorporate one or more further active ingredients.

[0034] A suitable daily dose of an active compound according to theinvention may for example be in the range 2 μg-400 mg per day, dependingon factors such as the severity of the condition being treated and theage, weight and condition of the subject.

[0035] Compounds according to the invention may be prepared by anyconvenient method, for example by reaction of a compound containing aprecursor for the desired 17-position side chain in one or more stagesand with one or more reactants serving to form the desired 17-positionside chain, followed if necessary and/or desired by removal of anyO-protecting group(s).

[0036] Thus, for example, compounds of the invention may be preparedfrom appropriately 2-substituted, e.g. 2-hydroxylated or 2-alkoxylated,derivatives of oestrone by, for example, Wittig reaction with anethylidene phosphorane to convert the 17-one to the corresponding17(20)Z-ethylidene compound, following the procedure described byKrubiner and Oliveto, J. Org. Chem. 31, pp. 24-26 [1965]. Alternatively,the corresponding E-isomer may be obtained following the procedure ofMidland and Kwon, Tetrahedron Lett. 23(20), pp. 2077-2080 [1982]. Thethus-obtained alkenes may be subjected to conventional stereospecifichydroboration reactions followed by oxidative work-up with alkalinehydrogen peroxide solution (Krubiner, op. cit.) to afford thecorresponding 20-ols, which may be oxidised to 20-ones with chromiumtrioxide (Krubiner, op. cit.). Wittig reaction withmethoxymethylenetriphenyl-phosphorane followed by hydrolysis of the enolether with aqueous acid gives a non-stereospecific compound (I) in whichX is a valence bond and Y is an aldehyde group. Reduction with sodiumborohydride gives a corresponding compound of formula (I) wherein X is avalence bond and Y is hydroxymethyl.

[0037] Compounds of the invention having a double bond at the16(17)-position may, for example, be prepared stereospecifically bysubjecting the appropriate E- or Z-17(20) ethylidene compound preparedas described above to a stereospecific ene reaction. For example, suchene reactions include treatment with formaldehyde, boron trifluoride andoptionally acetic anhydride (Batcho et al., Helv. Chim. Acta 64, pp.1682-1687 [1981]) to form compounds of formula (I) in which X is avalence bond and Y is hydroxymethyl or acetoxymethyl. In an alternativeene reaction, treatment with ethyl propiolate/diethyl aluminium chloride(Dauben and Brookhart, J. Am. Chem. Soc. 103, pp. 237-238 [1980])affords ethyl esters of Δ16,17 acids which may be reduced to givecompounds in which Y is hydroxymethyl. Where appropriate the Δ16,17compounds described above may be stereospecifically hydrogenated, e.g.catalytically, to form a single bond at the 16(17)-position.

[0038] The acetyl group in compounds in which Y is acetoxymethyl may beremoved by hydrolysis and replaced by a leaving group such as tosyloxy.Homologation reactions may then be performed to increase the size of X,these including (i) treatment with a metal cyanide, hydrolysing thecyano group to yield a carboxy group or reducing the cyano group (e.g.with a metal hydride reducing agent such as diisobutyl aluminiumhydride) to yield a carboxaldehyde group, and where appropriate reducingthe carboxy or carboxaldehyde group (e.g. using sodium borohydride orlithium aluminium hydride) to yield a hydroxymethyl group which may inturn be subjected to tosylation and, if desired, further nucleophilicdisplacement; and (ii) treatment with a metallated derivative of anester or thioester of acetic acid, with a derivative containing anothercarbanionic equivalent of acetic acid (e.g. a metallated derivative ofacetonitrile), or with a metallated malonate ester (in which lastinstance the reaction product is partially hydrolysed to yield amonoester which may be decarboxylated by heating to yield a carboxylateester), reducing the resulting ester or thioester product to an alcohol(e.g. using lithium aluminium hydride), and converting the resultinghydroxyl group to a leaving group, such as a tosylate group or a halogenatom, e.g. as hereinbefore described. Alternatively, compounds in whichY is a carboxaldehyde group may be homologated by Wittig reaction withmethoxymethylenetriphenyl-phosphorane followed by hydrolysis of theresulting enol ether, e.g. with aqueous acid.

[0039] It will be appreciated that such procedures may be repeated asneeded to yield compounds (I) in which X is a desired alkylene group.

[0040] Compounds where Y is a group —C(R⁴)(R⁵)OR¹ in which R⁴ and/or R⁵are other than hydrogen may be prepared by conventional means, forinstance from a corresponding aldehyde or ketone by reaction with anappropriate organometallic reagent, for example a Grignard reagent,metal acetylide, alkyl lithium or alkyl silane.

[0041] Compounds according to the invention may also be prepared from a2-unsubstituted oestrogen by building up the desired 17-position sidechain and then introducing the desired 2-substituent as a later step,for instance by following the procedures of Cushman et al. (op. cit.).The key 2-formyl compounds used in such procedures are convenientlyprepared by formation of a 3-methoxymethyl ether, selective lithiationat the 2-position and formylation with dimethylformamide according tothe procedure of Lovely et al. (op. cit.).

[0042] Sulphamoyl R¹ groups may be introduced by conventional methodssuch as reaction with an appropriate sulphamoyl chloride in the presenceof a mild base, e.g. as described by Schwartz et al. in Steroids 61, pp.710-717 [1996] or as described in WO-A-9933858. If, for example, it isdesired selectively to introduce a sulphamoyl group at the 3-position,any hydroxyl group in the 17-position side chain may be protected duringsulphamation, for example as a carboxylic ester (e.g. an acetate) or asa silyl ether; such protecting groups may subsequently be removed byhydrolysis without affecting the sulphamoyl group.

[0043] In general, O-protecting groups may, for example, be removed byconventional methods such as are well documented in the literature. Thusesterifying acyl groups may be removed by basic hydrolysis, e.g. usingan alkali metal alkoxide in an alkanol. Etherifying groups such as silylgroups may be removed by acid hydrolysis or treatment with a fluoridesalt, e.g. a tetraalkyl ammonium fluoride. The use of such acid-labilebut base-stable protecting groups may be of particular advantage duringhomologation steps to build up a desired side chain, in view of thestrongly basic conditions normally employed for such reactions.

[0044] The contents of all documents referred to in this specificationare incorporated herein by reference.

[0045] The following non-limitative examples serve to illustrate theinvention. All temperatures are in ° C.

Preparation 12-Methoxy-3-triisopropylsilyloxy-19-nor-pregn-1,3,5(10),17(20)Z-tetraene

[0046] Sodium hydride (294 mg, 50%) in dimethylsulphoxide (6 ml) wasstirred at 70° for 1 hour, then cooled to room temperature.Ethyltriphenylphosphonium iodide (2.75 g) in dimethylsulphoxide (10 ml)was added dropwise and the mixture was stirred for 30 minutes. Asolution of 2-methoxy-oestrone-3-triisopropylsilyl ether (600 mg,prepared by silylation of the 3-OH compound with triisopropylsilylchloride and imidazole in dichloromethane overnight at room temperature)in dimethylsulphoxide (10 ml) was added dropwise. The resulting solutionwas stirred for 30 minutes, whereafter the temperature was raised to 70°and stirring was continued overnight. The reaction mixture was thencooled and worked up. Separation and purification of the products bychromatography gave the title compound (125 mg, see below) and the 3-OHanalogue (300 mg): IR (CDCl₃) ν_(max) 1590, 3520 cm⁻¹; NMR (CDCl₃) δ0.9(s, 18-H's), 1.67 (d, ═CH—CH's), 3.8 (s, OCH's), 4.7-5.2 (q, ═CHMe),6.5, 6.7 (s, 1,4-H's).

[0047] Silylation of this 3-OH compound (300 mg) as above andpurification of the product by chromatography gave the title compound(370 mg): IR (CDCl₃) ν_(max) 1600 cm⁻¹; NMR (CDCl₃) δ0.9 (s, 18-H's),1.68 (d, ═CH—CH's), 3.7 (s, OCH's), 4.7-5.3 (q, ═CH—Me), 6.4, 6.6 (s,1,4-H's).

EXAMPLE 1 a)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraene-24-carboxylicacid methyl ester [Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃,X=(CH₂)₂, Y=CO,OCH₃, Δ16 Double Bond]

[0048] Ethyl aluminium dichloride (1.4 ml, 2.4 mmol, in toluene) wasadded dropwise to a solution of the product from Preparation 1 above(370 mg) in dichloromethane (4 ml) containing methyl acrylate (144 μl).The resulting mixture was stirred for 4 hours, whereafter further methylacrylate (144 μl) was added and stirring was continued overnight. Thereaction mixture was then worked up and the product was purified bychromatography to give the title compound (345 mg): IR (CDCl₃) ν_(max)1600, 1720 cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-H's), 3.6 (s, OCH's), 5.1-5.4(bs, 16-H's), 6.4, 6.58 (s, 1,4-H's).

b)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol[Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃, X=(CH₂)₂, Y=CH₂OH, Δ16Double Bond]

[0049] Lithium aluminium hydride (1 ml of a 1M solution in ether) wasadded dropwise to a solution of the ester from (a) above (265 mg) inether (5 ml), whereafter the reaction mixture was stirred for 30minutes, diluted with ether and quenched with wet sodium sulphate,giving crude title compound (248 mg): IR (CDCl₃) ν_(max) 1600, 3380-3660cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-H's), 3.3-3.8 (b, HOCH's), 3.7 (s, OCH's),5.1-5.4 (bs, 16-H's), 6.4, 6.6 (s, 1,4-H's).

c) 2-Methoxy-3-hydroxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol [formula(I): R¹=H, R²=CH₃O, R³=α-CH₃, X=(CH₂)₂, Y=CH₂OH, Δ16 Double Bond]

[0050] The title compound was prepared by desilylating the product of(b) above by treatment with tetrabutylammonium fluoride intetrahydrofuran at room temperature overnight: IR (CDCl₃) ν_(max) 1590,3200-3660 cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-Me), 1.15 (d, 21-Me), 3.4-3.7(t, 24-OH, OMe), 5.1-5.4 (ea m, 16-H), 6.5-6.63 (m, 1,4-H's).

d)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol-24-sulphamateester [Formula (I): R¹ (iPr₃)Si, R²=CH₃O, R³=α-CH₃, X=(CH₂)₃,Y=CH₂O.SO₂.NH₂]

[0051] Sulphamoyl chloride (60 mg) was added to a solution of thealcohol from (b) above (55 mg) and dimethylaminopyridine (62 mg) inmethylene chloride (2 ml), and the resulting mixture was stirred for 2hours. Work up and purification by preparative thin layer chromatographygave the title compound (60 mg): IR (CDCl₃) ν_(max) 1600, 3100-3600cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-Me), 3.7 (s, OMe), 3.9-4.4 (bt, 24-H's),4.5-5.0 (b, NH's), 5.1-5.5 (m, 16-H), 6.43, 6.63 (ea s, 1,4-H's).

e)2-Methoxy-3-hydroxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol-24-sulphamateester [Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=(CH₂)₃, Y=CH₂OSO₂NH₂]

[0052] The product from (d) above was desilylated as in (c) above toafford the title compound (39 mg): IR (CDCl₃) ν_(max) 1590, 3200-3600cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-Me), 1.08 (d, 21-H's), 3.8 (s, OMe),3.9-4.4 (bt, 24-H's), 4.5-4.9 (b, NH's), 4.9-5.5 (m, 16-H), 6.53, 6.67(ea s, 1,4-H's).

EXAMPLE 2 a)2-Methoxy-3-triisopropylsilyloxy-20α-acetoxymethyl-19-nor-pregna-1,3,5(10),16-tetraene[Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂OCOCH₃, Δ16 Double Bond]

[0053] A mixture of boron trifluoride etherate (6 μl) and aceticanhydride (0.66 ml) in dichloromethane (0.3 ml) was added dropwise to asolution of2-methoxy-3-triiso-propylsilyloxy-19-nor-pregn-1,3,5(10),17(20)Z-tetraenefrom Preparation 1 (0.20 g) in dichloromethane (1 ml) containing aceticanhydride (0.1 ml) and paraformaldehyde (13 mg). The mixture was stirredfor 2 hours, whereafter saturated sodium hydrogen carbonate was addedand stirring was continued for 3 hours. The product was isolated byextraction into dichloromethane and purified by chromatography to givethe title compound (205 mg): IR (CDCl₃) νhd max 1605, 1725 cm⁻¹; NMR(CDCl₃) δ0.73 (s, 18-H's), 1.97 (s, OCOCH's), 3.6 (s, OCH's), 3.7-4.3(b, 22-H's), 5.2-5.5 (bs, 16-H's), 6.4, 6.57 (s, 1,4-H's).

b)2-Methoxy-3-triisopropylsilyloxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂OCOCH₃]

[0054] A solution of the product from (a) above (205 mg) in ethanol (5ml) containing 5% platinum on carbon (40 mg) was stirred under hydrogenfor 18 hours. Filtration and removal of the solvent afforded the titlecompound mixed with unreacted starting material (195 mg): IR (CDCl₃)ν_(max) 1600, 1720 cm⁻¹; NMR (CDCl₃) δ0.73 (s, 18-H's [startingmaterial]), 0.8 (s, 18-H's [product]), 2.0 (s, OCOCH's), 3.6 (s, OCH's),3.4-4.3 (b, 22-H's), 5.1-5.5 (bs, 16-H's), 6.4, 6.6 (s, 1,4-H's).

c)2-Methoxy-3-triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃, X=valence bond, Y=CH₂OH]and2-methoxy-3-triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (I): R¹=(i-Pr)₃Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH,Δ16 Double Bond]

[0055] Lithium aluminium hydride (0.5 ml of a 1M solution in ether) wasadded dropwise to the product mixture from (b) above (195 mg) in ether(4 ml). The resulting mixture was stirred for 30 minutes, treated withwet sodium sulphate and worked up to give a crude mixture of the titlecompounds (175 mg): IR (CDCl₃) ν_(max) 1600, 3620 cm⁻¹; NMR (CDCl₃)δ0.73 (s, 18-H's [starting material]), 0.8 [s, 18-H's [products, ca. 1:1mixture]), 3.7 (s, OCH's), 3.2-3.7 (b, 22-H's), 5.1-5.5 (bs, 16-H's),6.4, 6.6 (s, 1,4-H's).

d) 2-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH] and2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (I): R¹=H, R²=CH₃O, R³=α-CR₃, X=valence bond, Y=CH₂OH, Δ16Double Bond]

[0056] The product mixture from (c) above (45 mg) in tetrahydofuran (0.3ml) was desilylated by treatment with tetrabuylammonium fluoride intetrahydrofuran (0.3 ml) at room temperature overnight to give the titlecompound: (28 mg, semi-purified by preparative thin layerchromatrography): IR (CDCl₃) ν_(max) 1600, 3400-3660 cm⁻¹; NMR (CDCl₃)δ0.73 (s, 18-H's [starting material]), 0.83 (s, 18-H's [products, ca.1:1 mixture]), 3.8 (s, OCH's), 3.2-3.7 (b, 22-H's), 5.2-5.5 (bs,16-H's), 6.4, 6.63 (s, 1,4-H's).

EXAMPLE 32-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (I): R¹=H, R²=CH₃O, R³=60 -CH₃, X=Valence bond, Y=CH₂OH, Δ16Double Bond]

[0057] The title compound was prepared from the product of Example 2(a)by the procedures of Example 2(c) and (d): IR (CDCl₃) ν_(max) 1580,3420-3660 cm⁻¹; NMR (CDCl₃) δ0.83 (s, 18-Me), 1.07 (d, 21-Me), 3.3-4.0(bm, 22-H's), 3.8 (s, OMe), 5.1-5.6 (bm, 16-H, OH), 6.47, 6.6 (2×d,1,4-H's).

EXAMPLE 42-Methoxy-3-hydroxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence bond, Y=CH₂O.CO.CH₃,Δ1054 16 Double Bond]

[0058] The title compound was prepared by desilylating the product ofExample 2(a) using the procedure of Example 2(d): IR (CDCl₃) ν_(max)1580, 3420-3660 cm⁻¹; NMR (CDCl₃) δ0.77 (s, 18-Me), 1.05 (d, 21-Me), 2.0(s, COMe), 3.2-4.3 (bm, 22-H's), 3.8 (s, OMe), 5.0-5.6 (bm, 16-H, OH),6.47, 6.6 (2×d, 1,4-H's).

EXAMPLE 52-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0059] A solution of the product from Example 3 (60 mg) in ethanol (6ml) containing 5% platinum on charcoal (20 mg) was stirred underhydrogen overnight, whereafter the catalyst was removed by filtration,the solvent was evaporated and the thus-obtained crude product waspurified by preparative thin layer chromatography to give the titlecompound (44 mg): IR (CDCl₃) ν_(max) 1580, 3420-3640 cm⁻¹; NMR (CDCl₃)δ0.73 (s, 18-Me), 1.07 (d, 21-Me), 3.3-3.7 (bm, 22-H's), 3.83 (s, OMe),6.5, 6.63 (2×d, 1,4-H's).

EXAMPLE 6 a)2-Methoxy-3-hydroxy-20α-acetoxymethyl-9-nor-pregn-1,3,5(10),16-tetraene-3-O-sulphamate[Formula (I): R¹=NH₂.SO₂, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂O.CO.CH₃, Δ16 Double Bond]

[0060] Sulphamoyl chloride (130 mg) was added to a solution of theproduct from Example 4 (84 mg) and di-tert.-butylaminopyridine (134 mg)in methylene chloride (5 ml), and the resulting mixture was stirredovernight. The mixture was then diluted with ether, washed with waterthen brine, and dried, whereafter the solvent was removed and the crudeproduct was purified by preparative thin layer chromatography to giveunreacted starting material (14 mg) and the title compound (61 mg): IR(CDCl₃) ν_(max) 1600, 1715, 3200-3500 cm⁻¹; NMR (CDCl₃) δ0.8 (s, 18-Me),2.0 (s, COMe), 3.6-4.3 (bm, 22-H's, OMe), 5.1-5.4 (bm, 16-H, OH), 6.77,6.9 (2×d, 1,4-H's).

b)2-Methoxy-3-hydroxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10)-triene-3-O-sulphamate[Formula (I): R¹=NH₂.SO₂, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂O.CO.CH₃]

[0061] The title compound is prepared by desilylating the product ofExample 2(b) in accordance with the method of Example 2(d) andsulphamoylating the thus obtained 3-hydroxy compound as in (a) above.Alternatively the product of (a) above may be hydrogenated in accordancewith the method of Example 2(b).

EXAMPLE 7 a)2-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-3-O-sulphamate[Formula (I): R¹=NH₂.SO₂, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH,Δ16 Double Bond]

[0062] The product from Example 6(a) (40 mg) in methanol (3 ml) amdwater (1 ml) containing sodium bicarbonate (38 mg) was stirredovernight. Work up and purification by preparative thin layerchromatography gave the title compound (16 mg): IR (CDCl₃) ν_(max)3200-3600 cm⁻¹; NMR (CDCl₃) δ0.83 (s, 18-Me), 3.3-3.83 (bm, 22-H's,OMe), 4.1-4.8 (bm), 5.2-5.6 (bm, 16-H, OH), 6.4, 7.1 (2×d, 1,4-H's).

b)2-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3-O-sulphamate[Formula (I): R¹=NH₂.SO₂, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0063] The title compound is prepared by hydrolysing the product ofExample 6(b) using the method of (a) above or by hydrogenating theproduct of (a) above using the method of Example 2(b).

EXAMPLE 8 a)3-Hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3,22-bis-methoxymethylether [Formula (I): R¹=CH₃OCH₂, R²=H, R³=α-CH₃, X=Valence Bond,Y=CH₂OCH₂OCH₃]

[0064] The corresponding 3,22-diol (850 mg), which may be prepared bydesilylating the product of Preparation 3(b) of WO-A-0068246, wasdissolved in tetrahydrofuran (23 ml) containing diisopropylethylamine(3.9 ml) and was treated in the cold (0°) with methoxymethyl chloride (1ml) added dropwise. The resulting mixture was allowed to warm to roomtemperature and was then refluxed overnight. Work up and purification bychromatography gave the title compound (900 mg): IR (CDCl₃) ν_(max) 1600cm⁻¹; NMR (CDCl₃) δ0.7 (s, 18-Me), 1.08 (d, 21-Me), 3.27, 3.37 (ea s,OMe), 4.5, 5.0 (ea s, OCH₂O), 6.5-7.3 (m, 1,2,4-H's).

b)2-Formyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3,22-bis-methoxymethylether [Formula (I): R¹=CH₃OCH₂, R²=H.CO, R³=α-CH₃, X=Valence Bond,Y=CH₂OCH₂OCH₃]

[0065] A solution of s-butyl lithium in tetrahydrofuran (3.3 ml, 4.3 mM)was added dropwise at −78° to a solution of the ether from (a) above(440 mg) in tetrahydrofuran (6.6 ml). The resulting solution was stirredat −78° for 2 hours, treated with anhydrous dimethylformamide (2 ml) andthen allowed to warm to room temperature overnight. Work up andpurification by chromatography gave the title compound (323 mg): IR(CDCl₃) ν_(max) 1600, 1730 cm⁻¹; NMR (CDCl₃) δ0.7 (s, 18-Me), 1.08 (d,21-Me), 3.3, 3.43 (ea s, OMe), 4.5, 5.13 (ea s, OCH₂O), 6.73, 7.57 (eas, 1,4-H's), 10.2 (s, O═CH).

c)2,3-dihydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3,22-bis-methoxymethylether [Formula (I): R¹=CH₃OCH₂, R²=HO, R³=α-CH₃, X=Valence Bond,Y=CH₂OCH₂OCH₃]

[0066] A solution of m-chloroperbenzoic acid (204 mg) in methylenechloride (2 ml) was added dropwise to a solution of the formyl compoundfrom (b) above (220 mg) in methylene chloride (4 ml) containing disodiumhydrogen phosphate (245 mg). The mixture was stirred overnight at roomtemperature and was then worked up to give a 2-formate intermediateproduct. This intermediate was dissolved in methanol (4 ml) and thesolution was deoxygenated with argon. Aqueous sodium hydroxide (1 ml,1M) was added and the resulting solution was stirred for 2 hours andthen brought to pH 7. Work up and purification by preparative thin layerchromatography gave the title compound (152 mg): IR (CDCl₃) ν_(max)1590, 3200-3600 cm⁻¹; NMR (CDCl₃) δ0.7 (s, 18-Me), 1.14 (d, 21-Me),3.27, 3.42 (ea s, OMe), 4.5, 5.0 (ea s, OCH₂O), 5.5-5.7 (bm, OH), 6.5,6.9 (ea s, 1,4-H's).

d)2-Ethoxy-3-hydroxy-2α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3,22-bis-methoxymethylether [Formula (I): R¹=CH₃OCH₂, R²=C₂H₅O, R³=α-CH₃, X=Valence Bond,Y=CH₂OCH₂OCH₃]

[0067] A solution of the 2-hydroxy compound from (c) above (90 mg) inanhydrous dimethylformamide (2.5 ml) containing anhydrous potassiumcarbonate (300 mg) was stirred for 10 minutes then treated with ethyliodide (378 mg) followed by tetrabutylammonium iodide (4 mg). Theresulting mixture was stirred for a further 5 hours, whereafter moretetrabutylammonium iodide (378 mg) was added and the mixture was stirredovernight. Work up and purification by preparative thin layerchromatography gave the title compound (72 mg): IR (CDCl₃) ν_(max) 1590cm⁻¹; NMR (CDCl₃) δ0.73 (s, 18-Me), 1.1 (d, 21-Me), 1.4 (t, Et), 3.35,3.5 (ea s, OMe), 3.7-4.7 (q, Et), 4.58, 5.08 (ea s, OCH₂O), 5.5-5.7 (bm,OH), 6.75 (s, 1,4-H's).

e) 2-Ethoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=C₂H₅O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0068] The bis-ether from (d) above (72 mg) in tetrahydrofuran, (1.6 ml)containing hydrochloric acid (0.8 ml, 6N) was stirred at roomtemperature for 2 days, after which time starting material was stillobserved to be present. Work up and purification by preparative thinlayer chromatography gave unreacted starting material (25 mg) and thetitle compound (20 mg): NMR (CDCl₃) δ0.72 (s, 18-Me), 3.2-3.7 (bm,22-H's), 3.7-4.3 (q, Et), 5.2-5.5 (bm, OH), 6.47, 6.61 (ea s, 1-,4-H's).

f) 2-Formyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=H.CO, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0069] A solution of the formyl compound from (b) above (100 mg) intetrahydrofuran (2 ml) was treated with hydrochloric acid (6 ml, 6N) andthe mixture was stored for 2 days at room temperature, after which timestarting material was observed still to be present. Work up andpurification by preparative thin layer chromatography gave the titlecompound (54 mg): IR (CDCl₃) ν_(max) 1600, 1650, 3100-3660 cm⁻¹; NMR(CDCl₃) δ0.8 (s, 18-Me), 3.2-3.9 (m, 22-H's), 6.6-7.2 (ea s, 1,4-H's),9.63 (s, O═CH).

g)2-Hydroxymethyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=HOCH₂, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0070] Lithium aluminium hydride (0.75 ml of a 1M solution intetrahydrofuran) was added dropwise to a solution of the 2-formylcompound from (f) above (32 mg) in tetrahydrofuran (1.5 ml) at 0°. Theresulting solution was allowed to warm to room temperature and was thenstirred for 3 hours. Work up and purification by preparative thin layerchromatography gave the title compound (10 mg): IR (CDCl₃) ν_(max)3500-3660 cm⁻¹; NMR (CDCl₃) δ0.73 (s, 18-Me), 3.2-3.8 (m, 22-H's),4.4-4.8 (bm, 2-CH₂OH), 6.6-7.2 (ea s, 1,4-H's).

h) 2-Propenyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃.CH═CH, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0071] The title compound is obtained by adding a solution of the2-formyl compound from (f) above in tetrahydrofuran to a solution of theylide formed by reacting ethyltriphenylphosphonium bromide intetrahydrofuran with lithium bis-trimethylsilylamide. Alternatively theprotected 2-formyl compound from (b) above may be reacted with the sameylide, followed by removal of the methoxymethyl protecting groups as in(f) above.

EXAMPLE 9 a)2-Methoxy-3-triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5,(10)-triene[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OH]

[0072] The 20α-acetoxymethyl product from Example 2(a) (360 mg) wasfirst deacetylated by treatment with lithium aluminium hydride (1.2 ml,2.5 eq.) in ether (7 ml) for 30 minutes at room temperature. Thethus-obtained crude 20α-hydroxymethyl compound (200 mg) was thenhydrogenated over 5% platinum on carbon (40 mg) in ethanol (10 ml).Filtration and removal of the solvent gave the title compound (175 mg):IR (CDCl₃) ν_(max) 1600, 3300-3640 cm⁻¹; NMR (CDCl₃) δ0.73 (s, 18-Me),3.1-3.5 (m, 22-H; s, OMe), 6.43, 6.6(ea s, 1,4-H's).

b)2-Methoxy-3-triisopropylsilyloxy-19-nor-pregn-1,3,5,(10)-triene-20α-carboxaldehyde[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CHO]

[0073] The alcohol from (a) above (175 mg) in methylene chloride (4 ml)was treated with pyridinium dichromate (165 mg) for 2.5 hours. As thereaction was observed to be incomplete (50%, thin layer chromatographycontrol) further pyridinium dichromate (165 mg) was added and thereaction mixture was stirred for a further 2.5 hours, by which time mostof the starting material was observed to have been consumed. Work up andpurification by preparative thin layer chromatography gave the titlecompound (125 mg): IR (CDCl₃) ν_(max) 1600, 1710 cm⁻¹; NMR (CDCl₃) δ0.73(s, 18-Me), 3.67 (s, OMe), 6.4, 6.6 (ea s, 1,4-H's), 9.38 (d, CH═O).

c)2-Methoxy-3-triisopropylsilyloxy-20α-(1-hydroxyethyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH(CH₃)OH]

[0074] Methyl magnesium bromide (0.53 ml of a 1.4M solution intetrahydrofuran/toluene) was added dropwise to a solution of thealdehyde from (b) above (125 mg) in ether at 0°. After 30 minutes at 0°and 30 minutes at room temperature the reaction was terminated byaddition of saturated aqueous ammonium chloride and the product wasworked up to give the title compound (125 mg): IR (CDCl₃) ν_(max) 1590,3500-3640 cm⁻¹; NMR (CDCl₃) δ0.7 (s, 18-Me), 3.3-3.67 (m, CHOH; s, OMe),6.4, 6.6 (ea s, 1,4-H's).

d)2-Methoxy-3-hydroxy-20α-(1-hydroxyethyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH(CH₃)OH]

[0075] The product from (c) above (45 mg) was desilylated by treatmentwith tetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml)(thin layer chromatography control, about 4 hours). Work up andpurification by preparative thin layer chromatography gave the titlecompound (24 mg): IR (CDCl₃) ν_(max) 1580, 3460-3640 cm⁻¹; NMR (CDCl₃)δ0.75 (s, 18-Me), 1.05 (d, 21-Me), 3.4-4.1 (m, CHOH; s, OMe), 6.5, 6.65(ea s, 1,4-H's).

e)2-Methoxy-3-hydroxy-2α-(1-hydroxyprop-2-ynyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=—CH(OH)C≡CH]

[0076] The title compound is prepared by treatment of the aldehyde from(b) above with sodium acetylide, followed by desilylation as in (d)above.

f)2-Methoxy-3-hydroxy-20α-(1-hydroxybut-3-ynyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I) : R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH(OH)CH₂C≡CH]

[0077] The title compound is prepared by treatment of the aldehyde from(b) above with propargyl aluminium reagent prepared as described inExample 3(b) of WO-A-0068246, followed by desilylation as in (d) above.

g)22-Methoxy-3-hydroxy-20α-(2-hydroxyprop-2-yl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=—C(OH)(CH₃)₂]

[0078] The title compound is obtained by oxidation of the20α-(1-hydroxyethyl) compound from (c) above using pyridinium dichromatein accordance with the method of (b) above, followed by reaction withmethyl magnesium bromide as in (c) above and desilylation as in (d)above.

h)2-Methoxy-3-triisopropylsilyloxy-19-nor-pregn-1,3,5(10)-triene-20β-carboxaldehyde[Formula (I) R¹=(i-Pr₃)Si, R²=CH₃O, R³=β-CH₃, X=Valence Bond, Y=CHO]

[0079] The title compound was obtained by isomerisation of the aldehydefrom (b) above by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene insimilar manner to that described in Preparation 5 of WO-A-9516672 andisolation of the newly formed isomer by chromatography (silica gel G,toluene/hexane, more polar isomer).

i) 2-Methoxy-3-hydroxy-19-nor-pregn-1,3,5(10)-triene-20β-carboxaldehyde[Formula (I): R¹=H, R²=CH₃O, R³=β-CH₃, X=Valence Bond, Y=CHO]

[0080] The title compound is formed by desilylation of the epi-aldehydefrom (h) above in accordance with the method of (d) above.

j) 2-Methoxy-3-hydroxy-20β-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=β-CH₃, X=Valence Bond, Y=CH₂OH]

[0081] The title compound is obtained by reduction of the epi-aldehydeproduct from (h) above with sodium borohydride, followed by desilylationas in (d) above.

k)2-Methoxy-3-triisopropylsilyloxy-20α-(2-oxoethyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₂, Y=CHO]

[0082] The title compound is prepared from the aldehyde product of (b)above by reaction with methoxymethylenetriphenyl-phosphorane followed byacid hydrolysis of the intermediate enol ether, in similar manner tothat described in Preparation 1 of WO-A-9945024.

l) 2-Methoxy-3-hydroxy-20α-(2-oxoethyl)-19-nor-pregn-1,3,5(10)-triene(Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=CH₂, Y=CHO]

[0083] The title compound is prepared by desilylation of the product of(k) above as in (d) above.

m)2-Methoxy-3-hydroxy-20α-(2-hydroxyethyl)-19-nor-pregn-1,3,5(10)-triene[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=CH₂, Y=CH₂OH]

[0084] The title compound is prepared by reduction of the aldehydeproduct of (k) above with sodium borohydride, followed by desilylationas in (d) above.

EXAMPLE 102-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-3,22-bis-O-sulphamate[Formula (I): R¹=NH₂.SO₂, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂OSO₂NH₂, Δ16 Double Bond]

[0085] Sulphamoyl chloride (62 mg) was added to a solution of theproduct from Example 3 (16 mg) and dimethylaminopyridine (60 mg) inmethylene chloride (1 ml), and the resulting mixture was stirredovernight. The mixture was then diluted with ether, washed with waterthen brine, and dried, whereafter the solvent was removed and the crudeproduct was purified by preparative thin layer chromatography to givethe title compound (10 mg): IR (CDCl₃) ν_(max) 1620, 3100-3600 cm⁻¹; NMR(CDCl₃) δ0.8 (s, 18-Me), 1.12 (d, 21-Me), 3.77 (OMe), 5.0-5.5 (bm,16-H), 6.73, 6.87 (ea s, 1,4-H's).

EXAMPLE 11 a)2-Methoxy-3-triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-22-O-sulphamate[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₃, X=Valence Bond,Y=CH₂OSO₂NH₂, Δ16 Double Bond]

[0086] Sulphamoyl chloride (60 mg) was added to a solution of2-methoxy-3-triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (I): R¹=(i-Pr₃)Si, R²=CH₃O, R³=α-CH₃, X=valence bond, Y=CH₂OH,Δ16 double bond, obtained from the first step of Example 9(a)] (50 mg)and dimethylaminopyridine (60 mg) in methylene chloride (2.5 ml) and theresulting mixture was stirred for 1 hour. The mixture was then dilutedwith ether, washed with water then brine, and dried, whereafter thesolvent was removed and the crude product was purified by preparativethin layer chromatography to give the title compound (55 mg): IR (CDCl₃)ν_(max) 1590, 3200-3500 cm⁻¹; NMR (CDCl₃) δ0.83 (s, 18-Me), 3.7 (s,OMe), 4.4-4.8 (bm, NH's), 5.2-5.5 (bm, 16-H), 6.4, 6.6 (ea s, 1,4-H's).

b)2-Methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-22-O-sulphamate[Formula (I): R¹=H, R²=CH₃O, R³=α-CH₃, X=Valence Bond, Y=CH₂OSO₂NH₂, Δ16Double Bond]

[0087] The silyl ether from (a) above (55 mg) was desilylated bytreatment with tetrabutylammonium fluoride in tetrahydrofuran at roomtemperature for 3 hours and worked up and purified by preparative thinlayer chromatography to give the title compound (30 mg): IR (CDCl₃)ν_(max) 1590, 3200-3600 cm⁻¹.

1. Compounds of formula (I)

in which: R¹ represents a hydrogen atom or an O-protecting group; R²represents a hydroxyl, lower alkoxy, carboxaldehyde, lower alk-1-enyl orhydroxy- or lower alkoxy-substituted lower alkyl group; R³ represents amethyl group having α- or β-configuration; X represents a C₁₋₃ alkylenegroup or a valence bond; Y represents a carboxaldehyde group or a groupof formula —C(R⁴)(R⁵)OR¹ where R¹ is as defined above and R⁴ and R⁵,which may be the same or different, are each selected from hydrogenatoms, alkyl, alkenyl and alkynyl groups such that the total carboncontent of R⁴ and R⁵ does not exceed three atoms, with the proviso thatX is a valence bond when both R⁴ and R⁵ are other than hydrogen; and thedotted line signifies that a double bond may optionally be present atthe 16(17)-position:
 2. Compounds as claimed in claim 1 wherein R²represents a hydroxy or lower alkoxy group and Y is a carboxaldehydegroup or a group of formula —C(R⁴)(R⁵)OR¹ where R¹ is as defined inclaim 1 and R⁴ and R⁵ both represent hydrogen atoms.
 3. Compounds asclaimed in claim 1 wherein Y is a group of formula —C(R⁴)(R⁵)OR¹ inwhich R¹ is as defined in claim 1, one of R⁴ and R⁵ is methyl, ethyl,vinyl, ethynyl or propargyl and the other is hydrogen, or R⁴ and R⁵ bothrepresent methyl groups.
 4. Compounds as claimed in any of the precedingclaims wherein each R¹ is selected from hydrogen atoms, lower alkylgroups and metabolically labile O-protecting groups.
 5. Compounds asclaimed in claim 4 wherein said metabolically labile O-protecting groupsare sulphamoyl groups.
 6. Compounds as claimed in any of the precedingclaims wherein R² is selected from methoxy, ethoxy, propoxy, vinyl,prop-1-enyl, but-1-enyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyland ethoxypropyl groups.
 7. The compounds:2-methoxy-3-hydroxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol;2-methoxy-3-hydroxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol-24-sulphamateester;2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-2α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene;2-methoxy-3-hydroxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10),16-tetraene;2-methoxy-3-hydroxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-3-O-sulphamate;2-methoxy-3-hydroxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10)-triene-3-O-sulphamate;2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-3-O-sulphamate;2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene-3-O-sulphamate;2-ethoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene;2-hydroxymethyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene;2-propenyl-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(1-hydroxyethyl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(1-hydroxyprop-2-ynyl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(1-hydroxybut-3-ynyl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(2-hydroxyprop-2-yl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-19-nor-pregn-1,3,5(10)-triene-20β-carboxaldehyde;2-methoxy-3-hydroxy-20β-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(2-oxoethyl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-(2-hydroxyethyl)-19-nor-pregn-1,3,5(10)-triene;2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-3,22-bis-O-sulphamate;and2-methoxy-3-hydroxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10),16-tetraene-22-O-sulphamate.8. Active compounds of formula (I) as claimed in any of the precedingclaims for use in management of neoplastic disease; as agents to promotewound healing; in treatment of bone diseases, autoimmune disease,host-graft reaction, transplant rejection, inflammatory diseases,neoplasias or hyperplasias, dermatological diseases, hypertension,rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairmentor senile dementia; in fertility control in human or animal subjects; inlowering elevated serum cholesterol or in management of disordersinvolving blood clotting.
 9. Active compounds of formula (I) as claimedin any of claims 1 to 7 for use as antiangiogenics.
 10. The use of anactive compound of formula (I) as claimed in any of claims 1 to 7 forthe manufacture of a medicament for use in management of neoplasticdisease; as agents to promote wound healing; in treatment of bonediseases, autoimmune disease, host-graft reaction, transplant rejection,inflammatory diseases, neoplasias or hyperplasias, dermatologicaldiseases, hypertension, rheumatoid arthritis, psoriatic arthritis,asthma, cognitive impairment or senile dementia; in fertility control inhuman or animal subjects; in lowering elevated serum cholesterol or inmanagement of disorders involving blood clotting.
 11. Pharmaceuticalcompositions comprising an active compound of formula (I) as claimed inany of claims 1 to 7 in admixture with one or more physiologicallyacceptable carriers or excipients.
 12. A method of treatment of a humanor non-human animal subject in the management of neoplastic disease; topromote wound healing; in treatment of bone diseases, autoimmunedisease, host-graft reaction, transplant rejection, inflammatorydiseases, neoplasias or hyperplasias, dermatological diseases,hypertension, rheumatoid arthritis, psoriatic arthritis, asthma,cognitive impairment or senile dementia; in fertility control; inlowering elevated serum cholesterol or in management of disordersinvolving blood clotting, which method comprises administering to saidsubject a therapeutically effective amount of an active compound offormula (I) as claimed in any of claims 1 to
 7. 13. A process for thepreparation of a compound of formula (I) as defined in claim 1 whichcomprises reacting a compound containing a precursor for the desired17-position side chain in one or more stages and with one or morereactants serving to form the desired 17-position side chain, followedif necessary and/or desired by reaction to introduce a desired2-substituent and/or to remove any O-protecting group(s).